Several clinical studies are underway to explore the cognitive effects and neurophysiologic underpinnings of nicotine withdrawal, as well as the effects of various nicotine dosage forms in reversing these effects. Neurophysiologic data indicate the mechanisms of the effects of nicotine and its withdrawal on neural substrates involved in attention, cognition and memory. For example, the effects of mecamylamine, a centrally acting nicotinic antagonist is studied to determine the contribution of tonic cholinergic mechanisms on the EEG and cognitive tasks in smokers and nonsmokers. The ability of transcranially delivered electrostimulation to alleviate nicotine withdrawal was evaluated in a treatment protocol. The efficacy of transdermally delivered nicotine to diminish signs and symptoms of tobacco spontaneous withdrawal are being further tested in a residential study. The interaction of caffeine and nicotine after overnight abstinence was assessed. Dependent measures for these studies include: Gordon vigilance task (with and without distracters), word memory, PAB (performance) spontaneous EEG, evoked potentials, blood pressure, heart rate (physiologic); withdrawal scales, craving, drug liking, drug identification (subjective). These studies are not only helping us to unravel the mechanisms of nicotine addiction but are also of practical value in the development of more effective medications for treating nicotine dependence and withdrawal.